910
J . Org. Chem. 1990,55,910-918
obtained by silica gel chromatography of a portion, eluting with 81:51: 1 dichloromethane-ethyl acetate-acetic acid followed by lyopholizationof a benzene solution to give a foam which collapsed to an oil on standing: [a]%D +22.39" (c = 1.0, EtOH); E1 MS m / z (relative intensity) 337 (M+) (2), 220 (35), 163 (100); 'H NMR (CDCl,) d 1.30 (s, 3 H, C(CH3), (minor rotamer)), 1.42 (s, 6 H, C(CH,), (major rotamer)), 2.90-3.2 (m, 2 H, P-CH,), 3.60 (s, 2 H, CH,), 3.69 (s, 3 H, OCH,), 3.90 (m, 0.3 H, a-CH (minor rotamer)), 4.09 (m, 0.7 H, a-CH (major rotamer)), 4.99 (d, 0.7 H, J = 8 Hz, NH (major rotamer)), 6.30 (m, 0.3 H, NH (minor rotamer)),7.15 (m, 2 H, ArH), 7.22 (m, 2 H, ArH). Anal. Calcd for CI7Hz3NO6: C, 60.52; H, 6.87; N, 4.15. Found: C, 60.28; H, 7.09; N, 3.97. ( S ) - a - [ [l,l-Dimethylethoxy)carbonyl]amino]-4-[2-( ( 1,ldimethylethoxy)-2-oxoethyl]benzenepropanoicAcid (8c). A solution of 1.471 g of 7c in 25 mL of methanol and 5 mL of 1 N sodium hydroxide solution was stirred at room temperature for 2 h. The mixture was acidified with a slight excess of hydrochloric acid, was diluted with 100 mL of ether and was washed with water and saturated sodium chloride solution. The residue obtained after filtration and evaporation was chromatographed over 100 g of silica gel, eluting with 4059:0.5 ethyl acetate-hexane-acetic acid, and the product-containing fractions were combined, evaporated, diluted with toluene, and evaporated finally under high vacuum to give 1.105 g (78%) of 8c as a white wax: +21.41" (C = 1.00, EtOH); 'H NMR (CDC13) d 1.42 (5, 9 H, C(CH3),), 1.44 (s, 9 H, C(CH3),), 3.07 (m, 1 H, P-CHH), 3.15 (m, 1 H, P-CHH), 3.50 (s, 2 H, ArCH,), 4.57 (m, a-CH), 4.93 (m, 1 H, NH), 7.14 (d, 2 H, J = 8 Hz, ArH), 7.21 (d, 2 H, J = 8 Hz, ArH).
Anal. Calcd for CzoHzsNO6:C, 63.31; H, 7.70; N, 3.69. Found: C, 62.94; H, 7.68; N, 3.65. The dicyclohexylaminesalt was crystallized from ether-hexane: mp 133-135 "C; [a]%D +35.9" (c = 1.02);FAE3 MS m/z 561 (M+ + H); 'H NMR (CDCI,) 6 1.15-1.50 (m, 28, cyclohexyl,C(CH,),), 1.62 (m, 2 H, cyclohexyl), 1.78 (m, 4 H, cyclohexyl), 1.95 (m, 4 H, cyclohexyl),2.90 (m, 2 H, 2 CHN), 3.10 (m, 1H, 8-CHH), 3.20 (m, 1H, P - o , 3.46 (s, 2 H, ArCH,), 4.70 (m, a-CH), 5.25 (m, 1 H, NH), 7.11 (d, 2 H, J = 8 Hz, ArH), 7.16 (d, 2 H, J = 8 Hz, ArH). Anal. Calcd for C32H5,N206:C, 68.54; H, 9.35; N, 5.00. Found: C, 68.39; H, 9.36; N, 4.95.
Acknowledgment. We thank members of the Physical Chemistry Department, Hoffmann-LaFtoche, Inc., for determination of the spectral and microanalytical data for the compounds reported herein. We thank Joseph Michalewsky for the enantiomeric purity determinations. We also thank Drs. W. Danho and R. W. Kierstead for their support and advice during the course of these studies. Registry No. la,86937-00-0; lb, 19391-35-6;IC, 4326-36-7; 2a,123993-19-1;2b,123993-20-4;2c,112766-18-4; 3a,123993-21-5; 3b,123993-22-6;4a,123993-23-7;4b,123993-24-8;5b, 123993-259; 5 ~ 123993-26-0; , 6b, 123993-27-1; 6c, 123993-28-2; GwDCHA, 123993-34-0;7b, 123993-29-3;7c, 123993-30-6;8b,123993-31-7; 8c, 123993-32-8;Sc-DCHA,123993-35-1;10, 123993-33-9;H,C=
CHCOOBu-t, 1663-39-4;(E)-Bu3SnCH=CHCOOMe,82101-74-4; Bu3SnCHzCH=CH2, 24850-33-7; H-Tyr-OH, 60-18-4.
Synthesis and 1,3-Dipolar Cycloaddition Reactions of Novel Heteropentalene Mesomeric Betaines, Pyrrolo[ 1,2-c]imidazole Mesomeric Betaines Branislav Musicki Department of Chemistry, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138 Received May 5, 1989
A series of novel heteropentalene mesomeric betaines, pyrrolo[ 1,2-c]imidazole mesomeric betaines (loa-i), were prepared by condensation of 2-formylpyrroles with aromatic imines. The mesomeric structures loa-i are proposed on the basis of spectral and microanalytical data and the results of their participation in 1,3-dipolar cycloaddition reactions. Peri-, regio-, and stereoselectivity of cycloadditions of mesomeric betaines loa-i with acetylenic (DMAD, ethyl propiolate, ethyl phenylpropiolate, benzyl phenylpropiolate, and phenylacetylene) and olefinic (dimethyl fumarate and dimethyl maleate) dipolarophiles have been studied. High periselectivity was observed in cycloadditions with both series of dipolarophiles, with the dipolarophile adding exclusively across the 1,3-azomethineylide dipole (10A). The respective formation of 2,2'-bipyrroles and 2',3'-dihydro-2,2'-bipyrroles in the cycloaddition of acetylenic and olefinic dipolarophiles could be rationalized by considering rearrangements of the expected bicyclic cycloadducts 16 and 19.
It has been demonstrated that there are 10 general types of neutral heteropentalenes which are isoconjugate with the pentalenyl dianion,' and in a more general way are considered as isoconjugate with even nonalternant hydrocarbon dianions." In Ramsden's classification of heteropentalenes,lb-'four of these general types are conveniently described as heteropentalene mesomeric betaines (1)For the reviews on chemical and physical properties of heteropentalene mesomeric betaines, see: (a) Cava, M. P.; Lakshmikantham, M. V. Acc. Chem. Res. 1975,8,139. (b) Ramsden, C. A. Tetrahedron 1977,33,3203.(c) Volz, H.; Kowarsch, H. Heterocycles 1977,7,1319. (d) Potts, K. T. In Special Topics in Heterocyclic Chemistry; Weissberger, A., Taylor, E. C., Eds.; Wiley: New York, 1977;Vol. XXX, pp 317-379. (e) Gleiter, R.; Bartetzko, R.; Brahler, G.; Bock, H. J. Org. Chem. 1978, 43, 3893. (0 Elguero, J.; Claramunt, R. M.; Summers, A. J. H. Adu. Heterocycl. Chem. 1978,22,183. (g) Potta, K. T. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; John Wiley & Sons: New York, 1984;Vol. 11, pp 1-82. (h) Ramsden. C. A. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984;Vol. VI, pp 1027-1048. (i) Ollis, W. D.; Stanforth, S. P.; Ramsden, C. A. Tetrahedron 1985,41, 2239.
0022-3263/90/1955-0910$02.50/0
of type A (l),type B (2), type C (3), and type D (4). These compounds are intrinsically interesting, particularly from the point of view of their electronic structure and their participation in l,&dipolar cycloaddition reactions. Most of the known heteropentalene mesomeric betaines are of type A and type B; very few examples of types C and D have been reported. Pyrrolo[ 1,2-c]imidazole mesomeric bentaine 3a belongs to the type C class of heteropentalene mesomeric betaines, and so far only one example of these class of compounds, 5, has been observed.'@ The betaine 5 was trapped by 2 equiv of dimethyl acetylenedicarboxylate (DMAD) to give the adduct 6. In continuing our investigation of the reaction of 2-formylpyrroles with ammonium salts and amines: we describe a general and (2)No experimental details were given for these observations in ref lh.
(3)Musicki, B.; Malley, M. F.; Gougoutas, J. Z. Heterocycles 1989,29, 1137.
0 1990 American Chemical Society
J. Org. Chem., Vol. 55, No. 3, 1990 911
Pyrrolo[1,2-c]imidazoleMesomeric Betaines
Table I. Preparation of Pyrrolo[ 1,2-c]imidazole Mesomeric Betaines loa-i
88-h
R H 7a-1 9
compd
R1
R2
7a
COOBn
Me
R3
COMe
compd
compd'
yields, %
Me
10a
61
Me
10b
86
Bu
1oc
38
Me Pr
1Oe
58 59
C-C6H11
1og
PhCHMe Me
10h 1Oi
R5
R4
Sa
Meoc$
COOBn H
7b
COOEt
Me
COOBn
8b H
7b
COOEt
Me
COOBn
8c
BnOOC COOEt
H
7d 7d 7d 7e 7f
COOEt
Me Me Me Me Me
COOEt COOEt COOEt COMe
COOEt COOEt
Se
Sf
COOEt
8g
COMe COOEt
8h 8e
Ph Ph o-MeOCBH4 Ph Ph
10f
51 36 50
OThe substituents R,-R, on mesomeric betaines loa-i corresDond to substituents R1-R3 of 2-formylpyrroles 7a-f and R4, R5 of imines -
1
Sa-h, respectively.
facile method for the synthesis of pyrrolo[ 1,2-c]imidazole mesomeric betaines and investigation of their 1,3-dipolar cycloaddition reactions.
Me-N
-9
b
N 5
:$ym.. MeOOC
COOMe
6
Results and Discussion 2-Formylpyrroles 7a-c with R1 and R3 as electronwithdrawing substituents4 (1 mol) easily undergo con(4) The presence of two electron-withdrawing substituents R1and R3 seems to be necessary for a successful condensation. No reaction was observed by heating at reflux 2-formylpyrrole (7) (R1= H, R2 = Me, R3 = Et; R1 = Me, R2 = Me, R3 = Et; R1 = Me, R2 = COMe, R3 = Me; R1 = Me, R2= COOBn, R3 = Et; R1= COOBn, % = COMe, R3 = Me) and 8e in benzene for 6 h. Only starting materials were recovered. Under the same reaction condtions, 7 (R1 = H, & = Me, R3 = COMe; R1= COOEt, R2 = Me, R3 = Me) afforded a complex mixture of products.
Scheme I
densation in the presence of primary aliphatic amines (0.5 mol) to afford pyrrolo[ 1,2-c]imidazolemesomeric betaines loa-d (Table I). Mechanistically, the reaction might proceed by initial formation of imine 8a-d: derived from reaction of 7a-c with the primary aliphatic amine. Condensation of 8a-d with unreacted 2-formylpyrrole 7a-c to give 2,3-dihydro-lH-pyrrolo[1,2-c]imidazole9, followed by dehydration and deprotonation, would afford the observed product 10A 10B. The condensations are performed simply by heating the 2-formypyrrole a t reflux with a primary amine in benzene or methanol. Other aromatic imines (8e-h) undergo similar condensation with 2formylpyrroles. The imines 8g,h required for the preparation of mesomeric betaines lOg,h were obtained by heating equimolar amounts of aromatic aldehyde and amine and were used directly in the condensation reaction without isolation and purification.
-
(5) It is known that simple 2-formylpyrroles react readily with primary amines to give the corresponding 2-pyrrylmethyleneimines." In the cases where it was impossible to isolate the imine, a Cu complex of the imine was prepared.6b (6) (a) Jones, R. A,; Bean, G. P. The Chemistry ojPyrroles; Academic Press: London, 1977; pp 295-303. (b) Yeh, K.; Barker, H. R. Inorg. Chem. 1967, 6 , 830.
912 J . Org. Chem., Vol. 55, No. 3, 1990
Musicki
Scheme I1
Table 11. UV-Visible and Fluorescence Properties of Pyrrole[ 1,2-c]imidazole Mesomeric Betaines loa-i absorbance A,
compd
1Oa
10b 12a.b
10b,e cornpd cornpd R,
R,
f%
R4
&
1oc 1Od
yields, %
COOBn Me
10b
1 2 8 COOEt Me COOBn
H 100
12bCOOEt Me
Ph
COOEt
1Oe Me
85
Me
42
10f
COOEt
The structures of pyrrole[ 1,2-c]imidazole mesomeric betaines loa-i are in complete agreement with spectroscopic and microanalytical data. The 'H NMR signal for the proton at the 1-position in mesomeric betaines loa-i appears as a sharp singlet at 6.50-7.00 ppm. This proton can be easily exchanged with deuterium in acidic media (CD30D/CD3COOD), demonstraing considerable delocalization of the negative charge to the 1-carbon, as described by mesomeric dipolar structure 10A (Scheme I). The 13C signal for the corresponding carbon atom appears in the range of 98-105 ppm. Use of Ph13CHNMe7in the condensation with 2-formylpyrrole 7d allowed isolation of 13C-enriched 10e and the chemical shift for the 3-carbon was assigned as 126.1 (s) ppm. The 13C chemical shift for the carbonyl carbon of the acetyl group in 1Oi (181.2 ppm) is comparable to the chemical shift of the acetyl carbonyl in 7f (189.1 ppm). Since the 13C chemical shifts of the a-carbons in enol ethers are in the range of 130-160 ppm? this excludes the alternative enol ether oxaaza[2.2.2]cyclazine structure (1 1) which could originate from 1Oi by
1og
10h 1Oi a
(log e ) , nm" emission ,A,, 502c
373 (4.48), 238 (4.49) 205 (4.45) 358 (4.58), 225 (4.61) 210 (460) 359 (4.45), 225 (4.55) 2.10 (4.54) 358 (4.45), 270 sh (4.15) 233 (4.58), 210 (4.66) 360 (4.43), 270 sh (3.93) 238 (4.24), 205 (4.27) 360 (4.41), 270 sh (3.95) 238 (4.24), 205 (4.30) 362 (4.44), 270 sh (3.94) 236 (4.23), 205 (4.37) 379 (4.44), 280 (3.83) 240 (4.20), 205 (4.40) 376 (4.34), 260 (4.21) 238 (4.14), 205 (4.29)
In CH,OH.
nmb
500d 500d 493d 463d 450d 459d 4Bd 452c
Excitation wavelength 350 nm.
In CC1,.
In
CHZC12.
Scheme I11
3
13
3A
t
m
k
14
38
11
loa-electron cyclization. Molecular models of mesomeric betaines loa-i show that the steric interactions between the phenyl or pyrrole ring at the 3-position and substituents at the 2- and 5-positions are relieved through rotations from a planar structure about the phenyl- or pyrrolepyrrolo[l,2-c]imidazole bond. This is reflected in a shielding effect (-0.5 ppm) observed for the CH, and CH2 protons of the COOEt, COMe, and COOBn groups at the 5-position in loa-c,e-i. A very low streching vibration of the CN group (2189 cm-') a t the 5-position in 10d [compared to the streching vibration of another CN group in 10d (2220 cm-') or the CN group of 2-formylpyrrole 7c (2228 cm-')I illustrates the contribution of mesomeric dipolar structure 10B. As further proof for the proposed structures of the mesomeric betaines, 10b,e were reduced with sodium cyanoborohydride in acetonitrile in the presence of acetic acid at room temperature to afford 2-(aminomethyl)pyrroles 12a,b,respectively (Scheme 11). Their structures were confirmed by independent synthesis (see the Experimental Section). (7) PhWHNMe (&), 99% I3C-enriched, was prepared from P h W H O and methylamine as described in ref 20. (8) Breitmaier, E.; Voelter, W. In Curbon-I3 NMR Spectroscopy; VCH: New York, 1987; pp 213-215, 278-279.
Regarding the electronic properties of interest, all mesomeric betaines loa-i display strong UV-visible absorption and fluorescence (Table 11). The structural features of the heteropentalene mesomeric betaines provide possibilities for diverse 1,3-dipolar cycloaddition reactions which would lead to unique monocyclic and ring-annulated heterocyc1es.Q Two dipolar azomethine ylide forms of pyrrole[ 1,2-c]imidazolemesomeric betaines, 3A and 3B (Scheme 111),could potentially participate in dipolar cycloaddition reactions. The cycloaddition of the dipolarophile across azomethine ylide 3A would lead to bicyclic product 13 (Scheme 111),whereas the addition across the azomethine ylide 3B would afford cycloadduct 14. When DMAD (15a) was added to a solution of mesomeric betaine 1Oe in benzene at room temperature, smooth conversion of the starting material occurred in 2 h, and the isolated product was characterized as 2,2'-bipyrrole 17a (Table 111) on the basis of its spectral properties. Formation of 17a can be rationalized by considering rearrangement of the expected bicyclic cycloadduct (16) formed by DMAD addition across the azomethine ylide dipole 10A. The exclusive participation of azomethine ylide dipole 10A in cycloaddition reactions was also observed with other acetylenic dipolarophiles (15b-e) (Table 111). The unsymmetrical dipolarophiles 15b,c underwent cycloaddition with high regioselectivity. Ethyl propiolate afforded 17b and 17c in the ratio 14:1, whereas phenylacetylene gave single regioisomer 17d. The regiochemistry of H and COOEt in 17b and H and Ph in 17d was determined by reaction of mesomeric betaine 10e, 13C-labeled
J . Org. Chem., Vol. 55, No. 3, 1990 913
Pyrrole[ 1,2-c]imidazole Mesomeric Betaines
Table 111. Cycloaddition of Acetylenic Dipolarophiles to Pyrrolo[ 1,2-c ]imidazole Mesomeric Betaines 15a MeO2CC=CCO2Me 15b E t 0 2 C C 3 C H 15c P h C l C H Rl&R
Y N \ H
R5 \
15d 15e PhC=CC02Et PhC=CCO2Bn * RZ4 7 3 # $ - - R 7
R $i-JR ;-
R7$ 4 ;
Rl
1 Ob,e,g
compd
compd
compd
R1
R2
R3
1Oe 1Oe
15a 15b
10e 1Oe
15c 15d
COOEt COOEt COOEt COOEt
10e
15e
log 10b
15a 15a
17a 17b 17c 17d 17e 17f 17g 17h 17i
Me Me Me Me Me Me Me Me Me Me
COOEt COOEt COOEt COOEt COOEt COOEt COOEt COOEt COOEt COOBn
17j
I
H
R,
R4
COOEt COOEt COOEt COOEt COOEt COOEt
16
17a.j R5
R6
R7
yields, %
Me Me Me Me Me Me Me Me c-CsH11 Me
COOMe H COOEt H COOEt Ph COOBn Ph COOMe COOMe
COOMe COOEt H Ph Ph COOEt Ph COOBn COOMe COOMe
83 31 2
R4 Ph Ph Ph Ph Ph Ph Ph Ph o-MeOC6H4 Me
BnOOC.
R5
59 62 14
65 15 28 53
&coo, H
a t the 3-position, with ethyl propiolate and phenylacetylene, respectively. According to Table 111,the isolated 17b and 17d were labeled at the 5’-position. The 13C NMR measurements of 13C-enriched samples of 17b and 17d provided the carbon-carbon coupling constants between C-5’ and the pyrrole carbon bearing the hydrogeng as ‘Jcc = 67.8 and 68.1 Hz, respectively. Since these are typical values for one-bond C-C coupling constants of aromatic carbon atoms,1° they indicate that the carbon bearing the hydrogen is in the 4’-position. The cycloaddition of ethyl and benzyl phenylpropiolate (15d,e) to 10e afforded both regioisomers in the respective ratios 17e:17f = 4.4:l and 17g:17h = 4.3:l. The location of substituents in 3’- and 4’-position in 17e-h was established as follows: hydrogenolysis of the benzyl ester 17g (1atm of HZ,10% Pd-C, MeOH) afforded carboxylic acid 17k (R, = COOH, R, = Ph). Decarboxylation of 17k was effected in 3% HC1EtOH at room temperature and afforded a product identical with 2,2’-bipyrrole 17d. Treatment of 17k with diazoethane in ether-THF at 0 “C provided 17e. The opposite regioselectivity in cycloaddition of 15b and 15d could be associated more with the steric influence of the phenyl group in mesomeric betaine 10e then with charge didtribution in azomethine ylide. Interestingly, the sterically hindered mesomeric betaine log reacts readily with DMAD to afford two rotational isomers of 17i in the ratio 58:42 based on the lH NMR spectrum (benzene-d,). The lH and 13C NMR spectra of 17i showed two sets of signals with very close chemical shift values. However, a single molecular ion peak was observed in the mass spectrum. Furthermore, ‘H NMR variabletemperature studies of 17i indicated the presence of a single rotational isomer a t 130 “C. We next investigated the 1,3-dipolar cycloaddition reaction of mesomeric betaine 10e with two olefinic dipolarophiles, dimethyl maleate (18a) and dimethyl fumarate (18b) (Scheme IV). On reaction in refluxing benzene, both 18a and 18b afforded mixtures of 2’,3’-dihydro-2,2’-bipyrroles 20a,b in the ratio 20a:20b = 8.4:l (78% and 8%) (9) The chemical shift of the pyrrole carbon bearing a hydrogen in 17b,d can be easily identified by proton selective decoupling experiments. (10) (a) Wray, V. In Progress in Nuclear Magnetic Resonance Spectroscopy; Emsley, J. W., Feeney, J., Sutcliffe, L. H., Eds.; Pergamon Press: Oxford, 1980; Val. XIII, pp 177-256. (b) Levy, G. C.; Lichter, R. L.; Nelson, G. L. In Carbon-13 Nuclear Magnetic Resonance Spectroscopy; John Wiley & Sons: New York, 1980; p 125.
Scheme IV
o*
18b R,-H. RpCO,Me
I
l@
Me 17s
20a R,-H, R,-COOMe
20b R,-COOMe. R,=H
and 5.3:1 (77% and E % )respectively. , The structures 20a,b are in agreement with spectroscopic data, and both isomers gave 2,2’-bipyrrole 17a on treatment with DDQ in CH,Cl, at room temperature. The position of the double bond in dihydropyrrole ring of 20a,b was unambiguously assigned, again through 13C-isotopiclabeling. The observed 13C chemical shifts of 13C-enriched 5’-carbons in 20a,b” are 163.7 (s) and 165.1 (s) ppm, respectively. The stereochemistry of the hydrogens at the 2’- and 3’-position in 20a,b was determined on the basis of NOE experiments and equilibration studies. In the case of cis isomer 20b, NOE enhancement was observed between H-2’ and H-3’ and between H-2’ and the N-methyl group. Trans isomer 20a displayed significant NOE enhancement only between H-2’ and the N-methyl group. Isomers 20a,b were respectively equilibrated in 0.2 M CH30Na/CH30H. After 5 days at room temperature, each isomer afforded the same ratio 20a:20b = 9:l. Formation of 20a,b can be explained by a mechanism (Scheme IV) similar to that proposed in Table I11 for the cycloaddition of acetylenic dipolarophiles. Here again, 10e behaves as a 1,3-azomethine ylide dipole (lOA), affording the bicyclic intermediate 19, which then rearranges to 20a,b. In order to establish that the observed (11) 2’,3’-Dihydro-2,2’-bipyrroles (20a,b) 99% %-enriched at 5’-position were prepared by reaction of 10e (Wlabeled at 3-position) with dimethylfumarate.
914 J. Org. Chem., Vol. 55, No. 3, 1990
Musicki
Scheme V
endo
ex0
M e O O C d /
endo
ex0
ratios 20a:20b are the result of endo or exo cycloaddition of 18a,b across the 1,3-azomethine ylide dipole (10A) and not to equilibration at the 3'-position of 20a or 20b under the reaction conditions, experiments were performed with 20a,b deuterium labeled a t the 2'-position (eq 1-4).12 I n lOe+lBa+20a-D 10e+18a+20b-D
10e+18b+20a-D
-
-
20a+20b+20a-D (20b-D not formed)
(1)
20a+20b+20b-D (20a-D not formed)
(2)
20a+20b+20a-D (20b-D not formed)
(3)
1 0 e + 1 8 b + 2 0 b - D -2Oa+20b+20b-D
(20a-D not formed)
(4)
each experimental run the amount of deuterated product (20a-D a n d 20b-D) used was approximately equal the amount of protiated product (20a) expected to be formed in cycloaddition reaction. After completion of the reaction, the isomers were separated a n d analyzed by lH N M R for the presence of 2Oa,b-D. T h e results clearly indicate that 20b equilibration under the reaction there is no 20a conditions. T h e course of the cycloadditions was also followed by 'H NMR spectroscopy (benzene-&) and no 18a 18b isomerization was observed. Assuming t h a t t h e stereochemistry of t h e starting olefins is retained in cycloadduct 19, 20a is t h e result of exo a n d endo cycloaddition of 18a a n d 18b, respectively, whereas 20b is the result of endo and exo cycloaddition of 18a and 18b, respectively (Scheme However, since t h e isolation of t h e intermediate 19 was not achieved, no decisive arguments can be advanced regarding t h e observed 20a:20b ratio. One plausible explanation, though, may be t h a t preferential formation of 20a in each case could be due to the involvement of reversible cycloadditions which under equilibrating conditions yield predominantly the thermodynamically favored trans isomer 20a (eq 5, 6).
v).
18s exo-19-10e-
18a
20a-
18b exo-l9=10e=
18b
20b-
endo-19-20b
(5)
endo-19-
(6)
20a
Concluding Remarks Quantitative theoretical studies of heteropentalene mesomeric betaines la-4a have been m a d e using HUckellhJ3 a n d CND0/21b methods. According to these calculations, t h e energy levels of t h e type C system (3a) are intermediate between those of type A (la) a n d B (2a) systems, a n d as a result, mesomeric betaine 3 should display the characteristics of both systems A (1) and B (2). (12) Deuterated 20a,b were prepared by the reaction of 1Oe deuterated a t the 1-position with dimethyl fumarate. The IH NMR spectra of POa,b-D indicated -95% deuterium enrichment. (13)Matsumoto, A.;Hee Lee, J.; Yoshida, M.; Simamura, 0. Bull. Chem. SOC.Jpn. 1974,47. 1490.
From t h e results of t h e cycloaddition reactions of substituted pyrrolo[ 1,2-c]imidazole mesomeric betaine derivatives loa-i with acetylenic a n d olefinic dipolarophiles, it is clear that the addition of these dipolarophiles is highly periselective a n d occurs exclusively across the 1,3-a20methine ylide dipole (10A). Therefore, the chemistry of t h e cycloaddition reactions of loa-i resembles that of the type A (1) mesomeric betaine systems. This result is complementary to the observation of Ramsden,lh who was able t o trap the species 5 by DMAD in a reaction which is characteristic of type B heteropentalene mesomeric betaines. A t this point, it is not clear whether the site selectivity in cycloadditions of loa-i is determined exclusively by the relative size of HOMO coefficients at the alternative site of addition or is also affected t o some extent by steric factors due to the presence of a substituent in the 5-position in 10a-i.14 T h e cycloaddition reactions of pyrrolo[ 1,2-c]imidazolemesomeric betaines with other dipolarophiles are currently under investigation in our laboratory.
Experimental Section General. The 'H NMR spectra were recorded at 300 and 500 MHz on Brucker AM-300 and AM-500 spectrometers,respectively. When CDC1, was used as the solvent, chemical shifts are reported in parts per million (ppm) downfield from tetramethylsilane as an internal standard. When benzene-d, was used as the solvent, chemical shifts are reported in reference to benzene (7.15 pprn). The 13C NMR spectra were recorded at 62,75, and 125 MHz on Brucker AM-250, AM-300, and AM-500 spectrometers, respectively. Chemical shifts are reported in parts per million in reference to CDC1, (77.00 ppm), benzene-de (128.00 ppm), or acetoned, (29.80 ppm). CDC1, used for NMR spectroscopy was passed through basic alumina before use. The IR spectra were recorded on a Nicolet 7199 FT-IR spectrometer. The electron impact (EI) mass spectra were recorded on a Kratos MS-5OL double-focusing mass spectrometer at 70 eV using direct insertion techniques. Chemical ionization (CI) mass spectra were recorded on the Kratos MS-50L using isobutane as the reagent gas. The fast atom bombardment (FAB) spectra were recorded on the Kratos MS-50L (gas, xenon; high voltage, 6 keV; matrix, mnitrobenzyl alcohol). The UV-visible spectra were measured on a Perkin-Elmer Model 124 double-beam spectrophotometer. Fluorescence spectra were measured on a Perkin-Elmer 4A fluorescence spectrometer. All melting points are uncorrected. Chromatographic separations were performed on open gravity columns with E. Merck Kieselgel60 (70-230 mesh). Preparative TLC (PTLC) separations were carried out on E. Merck precoated TLC plates (silica gel 60 F-254, layer thickness 0.5 mm). Commercial grade reagents were distilled before use. Pyrrolo[ 1,2-c]imidazole Mesomeric Betaine (loa). A solution of 2-formylpyrrole 7a15 (1.00 g, 3.51 mmol), methylamine hydrochloride (128.6 mg, 1.905 mmol), and anhydrous sodium acetate (156.2 mg, 1.905 mmol) in methanol (20 mL) was heated at reflux for 1 h. The solvent was evaporated, and the residue was dissolved in CHpC1,. The organic phase was washed with water and dried over MgSO,, then the solvent was evaporated. The residue was purified by column chromatography (hexanesEtOAc, 1:1,1:2) to afford loa (600 mg, 61%) as a brown oil: 'H NMR (300 MHz, benzene-d,) 6 1.81 (s, 3 H), 2.09 (s, 3 H), 2.62 (s, 3 H), 2.79 (s, 3 H), 2.90 (s, 3 H), 4.60 (d, 1 H, J = 12.4 Hz), 5.14 (d, 1 H, J = 12.4 Hz), 5.22 (d, 1 H, J = 12.5 Hz), 5.37 (d, 1 H, J = 12.5 Hz), 6.09 (br s, 1 H), 6.95-7.13 (m, 8 H), 7.40 (d, 2 H, J = 7.9 Hz), 13.18 (br s, 1 H); 13C NMR (125 MHz, CDCl,) 6 12.27 (q), 13.71 (q), 28.82 (q), 29.75 (q), 35.54 (q), 64.97 (t),66.26 (t), 104.71 (d), 108.28 (s), 119.14 (s), 121.84 (s), 123.20 (s), 127.58 (s), 127.83 (d), 127.83 (d), 127.88 (s), 128.18 (s), 128.25 (d), 128.25 (d), 128.46 (d), 128.46 (d), 128.92 (s), 135.73 (s), 135.84 (s), 136.48 (s), 160.12 (Y), 160.75 (s), 189.80 (s),194.15 (s);IR (neat) 3175-2894, 1714, 1682,1664,1613, 1563,1488,1455,1444,1396, 1284,1263, (14)Mok, K.-L.; Nye, M. J. J . Chem. Sac., Perkin Trans. 1 1975,1810. (15) Clesy, P.S.; Liepa, A. J. Aust. J . Chem. 1971,24,1933.
Pyrrolo[ 1,2-c]imidazole Mesomeric Betaines 1200,1106,1087cm-'; MS (FAB) m / e (relative intensity) 566 [(M 781, 565 (M', 81), 458 (24), 308 (8), 154 (39), 136 (37), 91 (100); HRMS (FAB) m / e (M+) calcd 565.2212, obsd 565.2198. Pyrrole[ 1,2-c]imidazole Mesomeric Betaine (lob). A solution of 2-formylpyrrole 7b16 (3.150 g, 10.0 mmol), methylamine hydrochloride (709 mg, 10.5 mmol), and anhydrous sodium acetate (861 mg, 10.5 mmol) in methanol (15 mL) was heated at reflux for 30 min. The solvent was evaporated, and the residue was dissolved in CHpCl,. The organic phase was washed with water and dried over MgSO,, and then the solvent was evaporated. The residue was triturated with methanol at 0 "C. Recrystallization from methanol afforded 10b (2.670 g, 86%) as a pale green solid: mp 193-194 "C; 'H NMR (300 MHz, benzene-@ 6 0.86 (t, 3 H, J = 7.0 Hz), 1.00 (t, 3 H, J = 7.0 Hz), 2.47 (9, 3 H), 2.94 (s, 3 H), 3.09 (s, 3 H), 3.73-3.79 (m, 1 H), 3.90-3.96 (m, 1 H), 4.11 (9, 2 H, J = 7.0 Hz), 4.64 (d, 1 H, J = 12.1 Hz), 4.82 (d, 1 H, J = 12.1 Hz), 5.36 (d, 1 H, J = 12.4 Hz), 5.75 (d, 1 H, J = 12.4 Hz), 6.41 (9, 1 H), 6.69-6.72 (m, 2 H), 6.91-6.97 (m, 3 H), 7.12-7.26 (m, 3 H), 7.56 (d, 2 H, J = 7.2 Hz), 11.25 (br s, 1 H); 13C NMR (125 MHz, acetone-d,) 6 11.73 (q), 13.38 (q), 14.63 (q), 14.83 (q), 35.87 (q), 59.33 (t),60.99 (t),64.66 (t),66.18 (t),92.74 (s), 105.13 (d), 108.34 (s), 118.65 (s), 119.53 (s), 122.33 (s), 125.26 (s), 128.40 (d), 128.61 (d), 128.61 (d), 128.61 (d), 129.04 (d), 129.24 (d), 130.37 (s), 136.59 (s), 136.85 (s), 139.20 (s), 143.47 (s), 160.92 (s), 161.36 (s), 163.79 (s), 164.30 (s); IR (KBr) 3186, 3160, 2978, 2949, 1717, 1700,1677,1653,1580, 1496, 1478,1455,1431,1402,1379,1293, 1261, 1209, 1173, 1120, 1089, 1058, 702 cm-'; MS (FAB) m / e (relative intensity) 626 [(M + H)', 371, 625 (M', 501, 580 (lo), 534 (6), 472 (lo), 154 (ll),91 (100). Anal. Calcd for C35H36N308: C, 67.19; H, 5.64; N, 6.72. Found: C, 67.40; H, 5.54; N, 6.69. Pyrrole[ 1,2-c]imidazole Mesomeric Betaine (1Oc). A solution of 2-formylpyrrole7b (630 mg, 2.00 mmol) and butylamine (87.6 mg, 1.20 mmol) in benzene (20 mL) was heated at reflux (Dean-Stark apparatus) for 2 h. The solvent was evaporated, and the residue was triturated with [(hexanes-EtOAc, 41)-methanol 1:1] at 0 "C. Recrystallization from methanol afforded 1Oc (252 mg, 38%) as a pale green solid: mp 140.5-141.5 "C; 'H NMR (300 MHz, CDCl,) 6 0.73 (t, 3 H, J = 7.2 Hz), 0.99-1.22 (m, 2 H), 1.06 (t, 3 H, J = 7.0 Hz), 1.31 (t,3 H, J = 7.1 Hz), 1.42 (quintet, 2 H, J = 7.4 Hz), 2.63 (s, 3 H), 2.69 (s, 3 H), 3.463.65 (m, 2 H), 3.78-3.98 (m, 2 H), 4.16-4.27 (m, 2 H), 4.80 (d, 1 H, J = 11.9 Hz), 4.92 (d, 1 H, J = 11.9 Hz), 5.19 (d, 1 H, J = 12.6 Hz), 5.43 (d, 1 H, J = 12.6 Hz), 6.57 (s, 1 H), 6.76-6.79 (m, 2 H), 7.01-7.06 (m, 3 H), 7.32-7.49 (m, 5 H), 10.68 (br s, 1H); 13CNMR (125 MHz, CDC13) 6 11.52 (q), 13.19 (q), 13.30 (q), 14.21 (q), 14.46 (q),19.40 (t), 31.71 (t),48.17 (t),59.18 (t),60.79 (t),64.80 (t),65.95 (t), 92.42 (s), 102.67 (d), 107.62 (s), 116.60 (s), 119.21 (s), 121.55 (s), 123.94 (s), 127.73 (d), 127.93 (d), 127.98 (d), 128.18 (d), 128.23 (d), 128.42 (d), 130.35 (s),135.00 (s), 135.86 (s), 137.59 (s),143.55 (s), 160.82 (s),161.30 (s), 163.15 (s), 164.49 (s); IR (KBr) 3194, 2960,2934, 1715, 1701, 1679, 1645, 1578,1456,1402, 1382, 1258,1196,1172,1127, 1091, 1056 cm-'; MS (FAB) m / e (relative intensity) 668 [(M + H)+,251, 667 (M+,33), 622 (7), 577 (5), 514 (6), 91 (100). Anal. Calcd for C38H41N308:C, 68.35; H, 6.19; N, 6.29. Found: C, 68.18; H, 6.10; N, 6.28. Pyrrole[ 1,2-c]imidazole Mesomeric Betaine (loa). A solution of 2-formylpyrrole 7c17 (600 mg, 2.13 mmol), methylamine hydrochloride (158.7 mg, 2.35 mmol), and anhydrous sodium acetate (192.8 mg, 2.35 mmol) in methanol (4 mL) was heated at reflux for 30 min. The solvent was evaported, and the residue was dissolved in CH2C12. The organic phase was washed with
+ H)',
(16) Howarth, T. T.; Jackson, A. H.; Judge, J.; Kenner, G. W.; Newman, D. J. J. Chem. SOC., Perkin Trans. 1 1974, 490. (17) 2-Formylpyrrole 7c was prepared by the following transformations: formylation of benzyl 4-ethyl-2-methylpyrrole-3-carboxylate's with HC(OEt)3in CF,COOH at room temperature afforded benzyl 5-formyl4-ethyl-2-methylpyrrole-3-carboxylate.The 5-formylpyrrole was then converted to the oxime, which was dehydrated in refluxing AczO to benzyl 5-cyano-4-ethyl-2-methylpyrrole-3-carboxylate. Treatment of 5-cyanopyrrole with SOzCl2(2 equiv) in AcOH at 50 OC followed by hydrolysis afforded 2-formylpyrrole (7c): mp 112.5-113.5 OC; 'H NMR (300 MHz, CDC13)6 1.21 (t, 3 H, J = 7.5 Hz), 2.90 (q,2 H, J = 7.5 Hz), 5.38 (s, 2 H), 7.35-7.44 (m, 5 H), 9.94 (br s, 1 H), 10.20 (s, 1 H); IR (KBr) 3220-2933, 2228, 1722, 1662, 1647, 1442, 1373, 1280, 1240, 1143, 1092 cm-'. Anal. Calcd for C,,H,,N,Og C, 68.07; H, 5.00; N, 9.92. Found: C, 68.15; H, 5.02; N, 9.84. (18)Roomi, M. W.; MacDonald, S. F. Can. J. Chem. 1970, 48, 1689.
J. Org. Chem., Vol. 55, No. 3, 1990
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water and dried over MgSO,, and then the solvent was evaported. The residue was purified by column chromatography (hexanesEtOAc, 4:l). Trituration with methanol at 0 "C and then recrystallization from methanol afforded 10d (531.8 mg, 89%) as a pale green crystals: mp 179.5-180.5 "C dec; 'H NMR (300 MHz, CDCl,) 6 1.05 (t, 3 H, J = 7.3 Hz), 1.28 (t, 3 H, J = 7.3 Hz), 2.17-2.31 (m, 2 H), 2.94-3.03 (m, 2 H), 3.47 (9, 3 H), 5.00 (d, 1 H,J=11.9Hz),5.13(d,lH,J=11.9H~),5.35(d,lH,J=l2.1 Hz), 5.58 (d, 1 H, J = 12.1 Hz), 6.48 (9, 1 H), 7.00-7.03 (m, 2 H), 7.15-7.17 (m, 3 H), 7.35-7.45 (m, 3 H), 7.53 (d, 2 H, J = 7.3 Hz), 12.05 (br s, 1 H); 13C NMR (125 MHz, CDC13) 6 14.93 (q), 15.17 (q), 19.11 (t),19.62 (t), 35.38 (q), 66.29 (t),66.67 (t),86.22 (s),89.59 (s), 104.77 (s), 105.48 (d), 112.18 (s), 113.74 (s), 115.31 (s), 117.86 (s),119.85 (s), 128.10 (d), 128.28 (d), 128.43 (d), 128.48 (d), 128.48 (d), 128.52 (d), 134.56 (s), 134.70 (s), 136.37 (s), 140.98 (s), 150.52 (s), 161.86 (s), 165.04 (s); 1R (KBr) 3142-2733, 2220, 2189, 1710, 1650,1579,1498,1470,1451,1292,1280, 1270,1227, 1158,1142, 1107 cm-'; MS (FAl3) m / e (relative intensity) 560 [(M + H)', 401, 559 (M+,49), 452 (8), 307 (18), 154 (loo), 91 (76). Anal. Calcd for C33H29N504:C, 70.82; H, 5.22; N, 12.52. Found: C, 70.50; H, 5.18; N, 12.45. Pyrrole[ 1,2-c]imidazole Mesomeric Betaine (10e). A solution of 2-formylpyrrole 7d19 (2.53 g, 10.0 mmol) and imine 8em (1.31 g, 11.0 mmol) in benzene (50 mL) was heated at reflux for 1 h. The solvent was evaporated, and the residue was separated by column chromatography (hexanes-EtOAc, lO:l, 6:1, 4:l) to afford 10e (2.04 g, 58%) as a pale green oil. Trituration and recrystallization from ether provided a pale green solid: mp 122-123 OC; 'H NMR (300 MHz, benzene-d,) 6 0.77 (t, 3 H, J = 7.1 Hz), 1.23 (t, 3 H, J = 7.1 Hz), 2.51 (s,3 H), 3.38 (9, 3 H), 3.81 (4, 2 H, J = 7.1 Hz), 4.41 (9, 2 H, J = 7.1 Hz), 6.72 (s, 1 H), 6.78-6.82 (m, 2 H), 6.99-7.04 (m, 3 H); 13CNMR (75 MHz, CDCl,) 6 12.98 (q), 14.13 (q), 14.71 (q), 35.86 (q), 58.51 (t),58.51 (t),92.03 (s), 103.44 (d), 106.85 (s), 126.11 (s), 127.63 (s), 127.96 (d), 129.24 (d), 129.42 (d), 136.10 (s), 144.47 (s),160.45 (s), 164.67 (s); IR (KBr) 2978,2946,2933,1687,1651,1619,1520, 1481, 1263, 1248,1191, 1176, 1133, 1097, 1059, 1015, 772 cm-'; MS (EI) m / e (relative intensity) 354 (M', 100), 326 (7), 309 (19), 282 (23), 254 (17), 210 (9), 105 (14), 77 (12). Anal. Calcd for C20HzzNz0,:C, 67.78; H, 6.26; N, 7.91. Found C, 67.50; H, 6.13; N, 7.85. 1Oe 13C-enriched; 13C NMR (75 MHz, CDC1,) 6 126.11 (SI, 3Jc.3,~.1 = 4.6 Hz. Pyrrolo[ 1,2-c]imidazole Mesomeric Betaine (10f). A solution of 2-formylpyrrole 7d (1.012 g, 4.00 mmol) and imine 8F' (647 mg, 4.40 mmol) in benzene (10 mL) was heated at reflux for 1 h. The solvent was evaporated, and the residue was separated by column chromatography (hexanes-EtOAc, 20:1, lO:l, 6:l) to afford 10f (895 mg, 59%) as a pale green oil: 'H NMR (300 MHz, CDCl,) 6 0.88 (t, 3 H, J = 7.5 Hz), 0.93 (t, 3 H, J = 7.1 Hz), 1.40 (t, 3 H, J = 7.1 Hz), 1.80 (sextet, 2 H, J = 7.4 Hz), 2.80 (s, 3 H), 3.76 (4, 2 H, J = 7.1 Hz), 3.92 (t, 2 H, J = 7.5 Hz), 4.33 (4, 2 H, J = 7.1 Hz), 6.98 (s, 1 H), 7.33-7.37 (m, 2 H), 7.45-7.50 (m, 3 H); 13CNMR (125 MHz, benzene-d,) 6 10.65 (q), 14.01 (q), 14.58 (q), 15.11 (q), 23.83 (t),49.58 (t),58.51 (t),58.80 (t), 93.07 (s), 102.16 (d), 107.42 (s), 125.55 (s), 127.91 (d), 128.69 (s), 129.23 (d), 130.01 (d), 137.07 (s), 144.07 (s), 160.56 (s), 164.82 (s); IR (neat) 2975, 2934,1692,1666,1619,1483, 1420,1403,1382,1271,1187, 1128, 1094 cm-'; MS (EI) m / e (relative intensity) 382 (M', loo), 354 (5), 337 ( l l ) , 310 (221, 282 (6), 105 (11);HRMS (EI) m / e (M') calcd 382.1893, obsd 382.1887. Pyrrolo[ 1,2-c]imidazole Mesomeric Betaine (log). A solution of o-methoxybenzaldehyde (749 mg, 5.51 mmol) and cyclohexylamine (521 mg, 5.25 mmol) in benzene (60 mL) was heated at reflux (Dean-Stark apparatus) for 30 min. The solution was cooled, and 2-formylpyrrole 7d (1.265 g, 5.00 mmol) was added. Heating at reflux was resumed for 3 h, and then the solvent was evaporated. The residue was separated by column chromatography (hexanes-EtOAc, 201,101,6:1) to afford log (1.29g, 57%) as a pale green oil: 'H NMR (500 MHz, CDC13) 6 0.96 (t, 3 H, J=7.1Hz),1.17-1.26(m,2H),1.40(t,3H,J=7.1Hz),1.69-2.04 (m, 8 H), 2.79 (s, 3 H), 3.70-3.89 (m, 3 H), 3.73 (s, 3 H), 4.33 (9, (19) Eisner, U.; Gore, P. H. J. Chem. SOC.1958, 922. (20) Moffett, R. B. Organic Syntheses; Wiley: New York, 1963; Collect. Vol. IV, p 605. (21) Campbell, K. N.; Helbing, C. H.; Florkowski, M. P.; Campbell, B. K. J. A m . Chem. SOC. 1948, 70, 3868.
916 J . Org. Chem., Vol. 55, No. 3, 1990
Musicki
Hz), 2.26 (s, 3 H), 2.55 (s, 6 H), 3.95 (s, 4 H), 4.29 (4, 4 H, J = 7.1 Hz), 5.29 (s, 4 H), 7.26-7.42 (m, 10 H), 9.95 (br s, 2 H); I3C NMR (75 MHz, CDCl,) 6 11.97 (q),14.43 (q), 43.80 (q), 54.30 (t), 60.34 (t), 65.73 (t), 113.60 (s), 119.03 (s), 128.07 (d), 128.19 (d), (q), 14.89 (q), 24.94 (t), 25.48 (t), 25.53 (t), 33.90 (t), 34.21 (t),55.36 128.54 (d), 130.78 (s), 136.49 (s), 139.29 (s), 161.31 (s), 164.88 (s); (q), 57.41 (d), 58.45 (t),58.57 (t),91.78 (s), 98.19 (d), 107.36 (s), IR (KBr) 3307, 3271, 2976, 2938, 1711, 1701, 1687, 1664, 1567, 110.67 (d), 116.99 (s), 119.96 (d), 122.51 (s), 130.91 (d), 131.41 (d), 1481,1446,1372,1298,1276,1254,1123,1089,776,732cm-'; MS 136.45 (s), 143.94 (s), 158.26 (s), 160.77 (s), 165.00 (s); IR (neat) (FAB) m/e (relative intensity) 630 [(M + H)', 301, 329 (131, 300 2934, 1690, 1665,1620,1518, 1483,1417, 1273, 1180,1133, 1115, (Zl), 91 (100). Anal. Calcd for C3,H39N308:C, 66.76; H, 6.24; 1093'cm-'; MS (EI) m/e (relative intensity) 452 (M', loo), 407 N, 6.67. Found: C, 66.68; H, 6.15; N, 6.68. (5), 379 (6), 318 (7), 251 (11); HRMS (FAB) m/e (M') calcd Independent Synthesis of 12a. To an ice-cold solution of 452.2311, obsd 452.2318. methylamine (33% aqueous solution, 0.75 mL) in ethanol (5 mL) Pyrrolo[ l,2-c]imidazole Mesomeric Betaine (10h). A sowas added ethyl 2-(chloromethyl)-3-(benzyloxycarbonyl)-4lution of benzaldehyde (570 mg, 5.37 mmol) and a-methylmethylpyrrole-5-carboxylate24 (1.00 g, 2.98 mmol). The mixture benzylamine (651 mg, 5.37 mmol) in benzene (20 mL) was heated was stirred at room temperature for 1 h and then was heated at at reflux (Dean-Stark apparatus) for 30 min. The solution was 60 "C for 30 min. The solution was cooled and then was poured cooled, and 2-formylpyrrole 7eZ2(1.090g, 4.89 mmol) was added. into cold water (50 mL). The precipitate was filtered and dried. Heating at reflux was resumed for 5 h, and then the solvent was Purification by column chromatography (hexanes-EtOAc, 20:1, evaporated. The residue was separated by column chromatoglO:l, 2:l) afforded 12a (621 mg, 66%) as a white solid. raphy (hexanes-EtOAc, lO:l, 4:1,2:1) to afford 10h (739 mg, 36%) Ethyl 2-[ (N-Benzyl-N-methylamino)methyl]-3-(ethoxyas a brown semisolid: 'H NMR (300 MHz, benzene-d,) 6 0.75 (t, carbonyl)-4-methylpyrrole-5-carboxylate (12b). In a manner 3H,J=7.1Hz),l.lO(d,3H,J=7.1Hz),2.45(s,3H),3.07(s, similar to the preparation of 12a, 12b was obtained from me3 H), 3.61-3.78 (m, 2 H), 4.90 (4, 1 H, J = 7.1 Hz), 6.58-6.61 (m, someric betaine 10e as colorless oil in 42% yield: 'H NMR (300 2 H), 6.87-7.02 (m, 8 H), 7.43 (br s, 1 H); 13C NMR (62 MHz, MHz, CDC1,) 6 1.35 (t,3 H, J = 7.1 Hz), 1.39 (t, 3 H, J = 7.1 Hz), benzene-d,) 13 14.45 (q), 14.75 (q), 21.52 (q), 30.01 (q), 57.19 (d), 2.29 (s, 3 H), 2.57 (s, 3 H), 3.60 (s, 2 H), 3.90 (s, 2 H), 4.27 (4, 2 58.66 (t), 100.63 (d), 106.10 (s), 107.52 (s), 125.90 (s), 126.03 (d), H, J = 7.1 Hz), 4.34 (4, 2 H, J = 7.1 Hz), 7.23-7.34 (m, 5 H), 9.66 128.06 (d), 128.11 (d), 128.76 (s), 128.96 (d), 129.55 (d), 130.25 (br s, 1 H); 13C NMR (75 MHz, CDCl,) 6 11.64 (q), 14.28 (q), 14.28 (d),137.24 (s),140.70(s),142.24 (s), 160.59 (s), 188.04 (s); IR (neat) (q), 42.91 (q), 53.86 (t),59.33 (t), 59.94 (t), 62.26 (t),112.97 (s), 2981,1676,1619,1516,1471, 1416,1403,1380,1202,1136cm-l; 118.25(s), 127.14 (d), 128.26 (d), 128.66 (d), 130.78 (s), 138.26 (s), MS (EI) m/e (relative intensity) 414 (M', 37), 310 (98), 238 (6), 140.25 (s), 161.17 (s), 165.05 (9); IR (neat) 3434, 2980, 1718, 1696, 160 (lo), 105 (100); HRMS (EI) m/e (M') calcd 414.1943, obsd 1568,1485,1445,1432,1371,1257,1232,1071,785,744,700 cm-'; 414.1936. MS (CI) m/e (relative intensity) 359 [(M + H)', 181, 313 (81, 267 Pyrrolo[ 1,2-c]imidazole Mesomeric Betaine (1Oi). A so(loo),238 (15), 221 (58), 175 (13), 120 (16), 91 (27); HRMS (FAB) lution of 2-formylpyrrole 7f3 (100.4 mg, 0.45 mmol), imine & (107.1 m/e (M') calcd 358.1893, obsd 358.1899 mg, 0.90 mmol), and acetic acid (54 mg, 0.90 mmol) in methanol Independent Synthesis of 12b. In a manner similar to the (6 mL) was heated at reflux for 4 h. The solvent was evaported, preparation of 12a, 12b was obtained from ethyl 2-(chloroand the residue was separated by PTLC (hexanes-EtOAc, 1:2) methyl)-3-(ethoxycarbonyl)-4-methylpyrrole-5-carboxyla~~ (273.5 to afford 10i (73 mg, 50%) as a plae brown solid. Recrystallization mg, 1.00 mmol) and N-methylbenzylamine (242.1mg, 2.00 mmol) from ether-EtOAc provided a sample for microanalysis: mp in ethanol (2 mL). The reaction was stirred at room temperature 159-160 "C; 'H NMR (300 MHz, benzene-d,) 6 1.25 (t,3 H, J = for 1 h and at 60 "C for 45 min, and then the solvent was evap7.1 Hz), 2.15 (s, 3 H), 2.55 (s, 3 H), 2.96 (s, 3 H), 4.41 (q, 2 H, J orated, and the residue was partitioned between CH,Cl, and water. = 7.1 Hz), 6.66 (s, 1 H), 6.86-6.90 (m, 2 H), 7.08-7.13 (m, 3 H); The organic layer was washed with water and dried over MgS04. I3C NMR (75 MHz, CDCl,) 6 13.78 (q), 14.64 (q),28.42 (q), 36.09 Purification by column chromatography (hexanes-EtOAc, 20:1, (q), 58.78 (t), 93.78 (s), 103.78 (d), 119.78 (s), 127.27 (d), 127.92 l O : l , 4:l) afforded 12b (327 mg, 91%) as a colorless oil. (s), 128.55 (s), 129.04 (d), 129.26 (d), 135.42 (s), 142.35 (s), 164.73 2,2'-Bipyrrole 17a. A solution of mesomeric betaine 1Oe (35.4 (s), 181.16 (s);IR (KBr) 3148, 3047, 2986, 1680, 1607, 1518, 1495, mg, 0.10 mmol) and DMAD (15.6 mg, 0.11 mmol) in benzene (3 1479, 1419,1389, 1238,1195, 1133,1092,771cm-'; MS (EI) m/e mL) was stirred at room temperature for 2 h. The solvent was (relative intensity) 324 (M', loo), 309 (6), 296 (9), 281 (21), 279 evaporated, and the residue was purified by PTLC [(2% (19), 252 (12), 208 ( 7 ) . Anal. Calcd for CISH,oN,O~:C, 70.35; CH,OH-CH,Cl,)-(hexanes-EtOAc, 2:1), 1:1] to afford 17a (41.2 H, 6.22; N, 8.64. Found: C, 70.22; H, 6.08; N, 8.70. mg, 83%) as a pink, viscous oil: 'H NMR (300 MHz, CDC13) 6 Deuterium Exchange Experiments on 10b and 10e. The 1.18 (t, 3 H, J = 7.2 Hz), 1.37 (t, 3 H, J = 7.2 Hz), 2.66 (5, 3 H), experiments were performed in the NMR tube. A solution of 3.24 (5, 3 H), 3.66 (s, 3 H), 3.68 (s, 3 H), 4.16 (q, 2 H, J = 7.2 Hz), mesomeric betaine 10b (4 mg) and CD,COOD (1 pL) in CD30D 4.30 (4, 2 H, J = 7.2 Hz), 7.35-7.38 (m, 2 H), 7.43-7.46 (m, 3 H), (600 wL) was heated at 80 "C (oil bath temperature) for 3 h. 9.95 (br s, 1 H); 13C NMR (75 MHz, CDC1,) 6 11.55 (q), 14.13 (q), During this time complete hydrogen-deuterium exchange at the 14.34 (q), 32.97 (q), 51.35 (q), 51.52 (q), 59.72 (t), 60.59 (t), 115.18 1-position occurred. In a similar experiment, complete hydro(s), 116.20 (s), 117.69 (s), 121.26 (s), 127.59 (s), 127.71 (s), 128.37 gen-deuterium exchange was observed when a solution of me(d), 128.90 (d), 130.43 (d), 130.43 (s), 130.66 (s), 137.56 (s), 161.09 someric betaine 1Oe (4 mg) and CD,COOD (1fiL) in CD30D (600 (s), 163.94 (s), 164.49 (s), 165.11 (s); IR (neat) 3260, 2984, 2951, FL) was kept at room temperature for 10 h.23 1716,1670,1483,1467,1256,1203,1172,1066 cm-'; MS (EI) m/e Ethyl 2-[ [ N - [[ 3-(Benzyloxycarbonyl)-5-(ethoxycarbonyl)-4-methylpyrrol-2-yl]methyl]-N-methylamino]- (relative intensity) 496 (M', loo), 464 (36), 450 (19), 419 (ll),118 (10); HRMS (EI) m/e (M') calcd 496.1845, obsd 496.1840. methyl]-3-(benzyloxycarbonyl)-4-methylpyrrole-52,2'-Bipyrroles17b and 17c. A solution of mesomeric betaine carboxylate (12a). To a solution of mesomeric betaine IOb (100 IOe (106.2 mg, 0.30 mmol) and ethyl propiolate (97.1 mg, 0.99 mg, 0.16 mmol) and acetic acid (300 pL) in acetonitrile (25 mL), mmol) in benzene (9 mL) was stirred at room temperature for stirring at room temperature, was added in portions NaBH,CN 8 h. The solvent was evaporated, and the residue was purified (300 mg, 4.77 mmol) over 3 h. The stirring was continued for 9 by column chromatography (hexanes-EtOAc, 1O:l) to afford 17b h, and then the solvent was evaporated. The residue was treated and 17c. Recrystallization of this mixture from hexanes-EtOAc, with CH,Cl,, and the organic phase was washed with water and 2:1, afforded pure 17b (38.5mg) as white crystals: mp 145.5-146.5 then saturated NaHC0, and was dried over MgS04. PTLC "C. Regioisomer 17c was isolated by PTLC (hexanes-tert-butyl separation (6% CH,OH-CH,Cl,) and recrystallization from methanol afforded l2a (85.7 mg, 85%) as white crystals: mp 120-121 "C; 'H NMR (300 MHz, CDClJ d 1.33 (t, 6 H, J = 7.1 2 H, J = 7.1 Hz), 7.00 (d, 1 H, J = 8.7 Hz), 7.01 (s, 1 H), 7.06 (t, 1 H, J = 7.3 Hz), 7.22 (dd, 1 H, J = 1.3, 7.4 Hz), 7.50 (dt, 1 H, J = 1.4, 8.0 Hz); 13C NMR (125 MHz, CDC1,) d 13.16 (q), 14.44
(22) Fischer, H.; Adler, E. Hoppe-Seyler's 2. Physiol. Chem. 1932,210, 139. (23) Prolonged exposure of mesomeric betaines (loa-i) to acidic con-
ditions leads to their slow decomposition.
(24) Ethyl 2-(chloromethyl)-3-(benzyloxycarbonyl)-4-methylpyrrole5-carboxylate was prepared by treatment of ethyl 4-(benzyloxycarbonyl)-3,5-dimethylpyrrole-2-carboxylate with S02C12 (1 equiv) in CH,Cl, a t 0 "C. (25)Corwin, A. H.; Bailey, W. A,, Jr.; Viohl, P. J . Am. Chem. SOC. 1942, 64, 1267.
Pyrrolo[ 1,2-c]imidazole Mesomeric Betaines
J. Org. Chem., Vol. 55, No. 3, 1990 917
131.35(s), 133.89(s), 135.02(s), 161.14(s), 164.26(s), 164.44(9); methyl ether, 2:1,eluting two times) of the mother liquor as a IR (neat) 3268,2982,2936,1706,1700,1697,1670,1507,1473, colorless, viscous oil (3 mg, 2%). Additional amount of 17b (3 1258,1203,1136,1069,732cm-'; MS (EI) m / e (relative intensity) mg, 31% total) was also isolated during PTLC separation of the 528 (M+, loo), 482 (43),452 (lo), 118 (7);HRMS (EI) m / e (M+) mother liquor. 17b 'H NMR (500MHz, CDC13) 6 1.11 (t,6H, calcd 528.2260,obsd 528.2250. J = 7.1Hz), 1.35(t, 3 H, J = 7.1Hz), 2.67(s, 3 H), 3.41(s, 3 H), 2,T-Bipyrroles 17g and 17h. A solution of mesomeric betaine 4.07(4, 2 H, J = 7.1Hz), 4.13(q, 2 H, J = 7.1Hz), 4.31(4, 2 H, 1Oe (106.2mg, 0.30mmol) and benzyl phenylpropiolate (944mg, J = 7.1Hz), 6.75 (s, 1 H), 7.35-7.45(m, 5 H), 9.74(br s, 1 H); 4.0mmol) in benzene (9mL) was heated at reflux for 14 h. The 13CNMR (125MHz, CDCl3) 6 11.71(q), 14.03(q), 14.03(q), 14.36 solvent was evaporated, and the residue was purified by column (q), 33.22(q), 59.55(t),59.58(t),60.52(t),110.11 (d), 115.73(s), chromatography (hexanes-EtOAc, 101,8:1)to afford 17g (115.9 116.85(s), 120.59(s), 127.77(d), 128.56(d), 128.94(d), 129.38(s), mg, 65%) and 17h (26.0mg, 15%) as colorless, viscous oils. 17g: 129.44(s), 130.47(s), 132.12(s), 135.94(s), 161.32(s), 164.21(s), 164.27(9); IR (neat) 3275,2980,2926,1714,1685,1476,1254,1204, 'H NMR (300MHz, CDCl,) 6 1.22(t, 3 H, J = 7.1Hz), 1.26(t, 3 H, J = 7.1 Hz), 2.58 (9, 3 H), 3.17 (s,3 H), 4.20(9, 2 H, J = 1066,764 cm-'; MS (EI) m / e (relative intensity) 452 (M+, loo), 7.1 Hz), 4.21(9, 2 H, J = 7.1 Hz), 4.93(s, 2 H), 6.70-6.73(m, 2 406 (54),361 (IO), 305 (5).Anal. Calcd for CZ5HBN2Os:C, 66.36; H), 7.09-7.20(m, 8 H), 7.37-7.45(m, 5 H), 9.18(br s, 1 H); 13C H, 6.24;N, 6.19. Found: C, 66.12;H, 6.40;N, 5.76. 17b, 13Cenriched: 13C NMR (125MHz, CDC13) 6 135.94(s), 2 J ~ . 5 / , ~ . 4-r NMR (75MHz, CDC13) 6 11.66(q), 14.20(q), 14.25(q), 32.68(q), 59.64(t),60.58(t), 65.23 (t),111.91(s), 117.94(s), 120.51(s), 123.04 7.1Hz, 1Jc.5,,c.4, = 67.8Hz. 17c: 'H NMR (500MHz, CDC13) 6 (s), 126.42(d), 126.97(s),127.30(d), 127.52(d), 127.61(d), 127.92 1.13(t, 3 H, J = 7.1Hz), 1.23(t, 3 H, J = 7.1 Hz), 1.39(t, 3 H, (d), 128.14(d), 128.44(d), 129.38(s), 129.85(d), 130.29(s), 130.51 J = 7.1Hz), 2.65(s, 3 H), 3.25(s, 3 H), 4.12(4, 2 H, J = 7.1Hz), (d), 132.05(s), 134.45(s), 135.98(s), 139.57(s), 161.32(s),164.10 4.21(4, 2 H, J = 7.1Hz), 4.36(4, 2 H, J = 7.1Hz), 6.81(s, 3 H), (s), 164.34(s);IR (neat) 3263,2981,2938,1708,1668,1469, 1444, 7.37-7.39(m, 2 H), 7.41-7.47(m, 3 H), 9.05 (br s, 1 H); 13CNMR 1378,1255,1151,1062,1009,759 cm-'; MS (EI) m / e (relative (125MHz, CDCl3) 6 11.80(q), 14.14(q), 14.25(q), 14.46(q), 32.96 intensity) 590 (M+,100),544 (23),528 (9),437 (7),91(43);HRMS (q), 59.46(t),59.86(t), 60.63(t),112.17(d), 113.17(s),116.49(s), (EI) m / e (M+)calcd 590.2417,obsd 590.2426.17h 'H N M R (500 120.23(s), 124.58(s), 128.05(d), 128.55(d), 129.98(s), 130.58(d), MHz, CDC13)6 1.19(t, 3 H, J = 7.1Hz), 1.37(t, 3 H , J = 7.1Hz), 130.87(s), 131.69(s), 140.28(s), 160.95(s), 164.24(s), 164.36(s); 2.62(s, 3 H) 3.29 (9, 3 H), 4.17 (4, 2 H,J = 7.1Hz), 4.30 (br q, IR (neat) 3267,2981,2934,1703,1651,1553,1468,1373,1254, 2 H), 4.94(s, 2 H), 6.85(d, 2 H, J = 6.6Hz), 7.14-7.22(m, 8 H), 1197,1100,1061,1037,776 cm-'; MS (EI) m / e (relative intensity) 7.26-7.30(m, 5 H), 9.25(br s, 1 H); 13CNMR (125MHz, CDCl,) 452 (M+,100),406 (74),361 (lo),305 (E)277 , (12),118(14),105 6 11.67(q), 14.19(q), 14.42(q), 33.15(q), 59.63(q), 60.42(q), 65.70 (21);HRMS (EI) m / e (M+)calcd 452.1947,obsd 452.1944. 17c, (q), 114.12(s), 117.04(s), 120.62(s),124.72(s),126.20(d), 127.40 %-enriched: 13CNMR (125MHz, CDCl3) 6 140.28(s),3JC.5,,H.3, (d), 127.60(d), 127.87(d), 128.01(d), 128.04(d), 128.27(d), 129.33 = 6.1 Hz. (s), 130.47(s), 130.81(d), 130.99(d), 131.15(s), 133.99(s), 134.83 %,2'-Bipyrrole17d. A solution of mesomeric betaine 1Oe (70.8 (s), 135.73 (s), 160.85 (s), 164.04(s), 164.15(s); IR (neat) 3266, mg, 0.20 mmol) and phenylacetylene (372 mg, 3.64mmol) in 2981,2935,1707,1700, 1697,1685,1457,1379,1256,1203,1130, benzene (3mL) was heated at reflux for 24 h. The solvent and 1069cm-'; MS (EI) m / e (relative intensity) 590 (M', 100), 544 excess phenylacetylene were evaporated, and the residue was (13), 482 (13),118 (lo), 91 (47);HRMS (EI) m / e (M+) calcd purified by column chromatography (hexanes-EtOAc, 1O:l) to 590.2417,obsd 590.2410. afford 17d (54.2mg, 59%) as a pale yellow oil: 'H NMR (300 2,2'-Bipyrrole 17i. A solution of mesomeric betaine log (45.2 MHz, CDC1,) 6 1.12(t, 3 H, J = 7.1Hz), 1.33(t,3 H, J = 7.1Hz), mg, 0.10mmol) and DMAD (17.0mg, 0.12mmol) in benzene (3 2.70 (s, 3 H), 3.42 (9, 3 H), 4.16(q, 2 H, J = 7.1 Hz), 4.29 (4, 2 mL) was stirred at room temperature for 8 h. The solvent was H, J = 7.1 Hz), 6.51 (s, 1 H), 7.12-7.50(m, 10 H), 8.95 (br s, 1 evaporated, and the residue was purified by PTLC (hexanesH); 13C NMR (75MHz, CDC1,) 6 11.70(q), 14.06(q), 14.28(q), EtOAc, 2:l)to afford 17i (16.7mg, 28%) as a colorless oil: 'H 32.77(q),59.54(t),60.47(t),107.98(d), 117.72(s), 120.62(s), 121.65 NMR (500 MHz, benzene-d,) 6 0.53-0.56 (m), 0.64478 (m), (s), 125.16(s), 125.59(d), 126.61(d), 127.28(d), 128.40(d), 128.48 0.89-0.93(m), 0.97(t, 3 H, J = 7.2Hz), 0.99(t, 3 H, J = 7.1),1.01 (d), 128.87(d), 130.83(s),130.88(s), 133.11(s), 135.46(s), 136.37 (t, 3 H, J = 7.0Hz), 1.06 (t, 3 H, J = 7.1 Hz) 1.28-1.40(m), (s), 161.22(s), 164.28(s); IR (neat) 3269,2981,2930,1702,1670, 1.52-1.58(m), 1.75(br d), 1.82(br d), 1.91(br d), 2.02(br d), 3.00 1556,1509,1481,1467,1382,1265,1250,1068,758,734,699; MS (s, 3 H), 3.02 (9, 3 H), 3.26(s, 3 H), 3.29 (s, 3 H), 3.39 (s, 3 H), (EI) m / e (relative intensity) 456 (M', 86),410 (loo), 309 (6),105 3.40(s, 3 H), 3.41 (s, 3 H), 3.42(s, 3 H),3.72-3.81(m), 3.92-4.12 (28);HRMS (EI) m / e (M+)calcd 456.2049,obsd 456.2042. 17d, (m), 4.22-4.26(m), 6.55(d, 1 H, J = 8.2Hz), 6.58(d, 1 H, J = %-enriched: 13C NMR (75MHz, CDC13) 6 136.37(s),2 J ~ . 5 , , ~ . 4 , 8.2Hz), 6.88(dt, 1 H, J = 0.9,6.8Hz), 6.89(dt, 1 H, J = 0.8, 7.0 = 6.9 Hz, 'JC.5t,c.4, = 68.1Hz. Hz), 7.13-7.18(m, 2 H), 7.38(dd, 1 H, J = 1.7,7.4Hz), 7.50(dd, %,2'-Bipyrroles17e and 17f. A solution of mesomeric betaine 1 H, J = 1.7,7.5Hz), 10.05(br s, 1 H), 10.25(br s, 1 H); 13CNMR 1Oe (106.2mg, 0.30mmol) and ethyl phenylpropiolate (697mg, (125MHz, benzene-d6)6 12.10(q), 12.16(q), 13.83(q), 14.11(q), 4.0mmol) in benzene (9mL) was heated a t reflux for 20 h. The 14.21 (q), 14.21(q), 25.30(t), 25.30(t), 26.40(t),26.50(t),26.50 solvent was evaporated, and the residue was purified by column (t),26.76(t), 33.20(t),33.30(t), 33.39 (t), 33.51(t),51.06(q), 51.10 chromatography (hexanes-EtOAc, 101,8:1) to afford 17e (98.1 (q), 51.19 (q), 51.26 (q), 55.00 (q), 55.00(q), 59.55 (t), 59.67 (t), mg, 62%) and 17f (22.3mg, 14%) as a colorless, viscous oils. 17e: 60.06(d), 60.08 (d),60.79(t),60.90(t), 110.96(d), 111.31(d), 116.39 'H NMR (300MHz, CDC1,) 6 0.79 (t, 3 H, J = 7.1Hz), 1.21 (t, (s), 116.60(s), 118.49(s), 118.56(s), 119.01(s), 119.16(s), 120.42 3 H, J = 7.1Hz), 1.28(t, 3 H, J = 7.1Hz), 2.60(s, 3 H), 3.16 (s, (d), 120.54(d), 121.05(s), 121.41(s), 121.46(s), 121.50(s), 126.50 3H),3.89(q,2H,J=7.1H~),4.20(q,4H,J=7.1H~),7.11-7.25 (s), 126.63(s), 129.75(s), 129.92(s),130.29(s), 130.35 (s), 130.79 (m, 5 H), 7.38-7.49(m, 5 H), 9.57(br s, 1 H); 13CNMR (75MHz, (d), 130.79(d), 133.02(d), 133.94(s), 133.98(s), 134.13(d), 158.37 CDCl,) 6 11.60(q), 13.44(q), 14.20(q), 14.20(q), 32.59(q), 59.12 (s), 158.96(s), 162.00(s), 162.13(s), 164.07(s), 164.13(s), 164.41 (t),59.58(t),60.55(t),112.40(s), 117.97(s), 120.49(s), 122.84(s), (s), 164.64(s), 165.07(s), 165.19(s); IR (neat) 3254,2940,1717, 126.28(d), 126.83 (s), 127.31 (d), 127.95(d), 128.32 (d), 129.55 1669,1551,1465,1321,1256,1169,1066 cm-'; MS (EI) m / e (s), 129.81(d), 130.27(s), 130.51(d), 132.16(s), 134.53(s), 139.30 (relative intensity) 594 (M+, loo), 563 (8), 562 (8), 512 (18),466 (s), 161.36(s), 164.10(s), 164.58(s); IR (neat) 3264,2981,2937, (20), 135 (33); HRMS (EI) m / e (M') calcd 594.2577,obsd 1706,1670,1508,1469,1384,1292,1255,1155,1130,760 cm-'; MS 594.2567. (EI) m / e (relative intensity) 528 (M', 100), 482 (52),129 (71,118 2,2':5',2"-Terpyrrole 17j. A solution of mesomeric betaine 10b (9);HRMS (EI) m / e (M+) calcd 528.2260,obsd 528.2254.17f (30.0mg, 0.048mmol) and DMAD (7.5mg, 0.053mmol) in benzene 'H NMR (300MHz, CDC13) 6 0.87(t, 3 H, J = 7.1Hz), 1.21 (t, (3mL) was heated at reflux for 15 min. The solvent was evap3 H,J = 7.1Hz), 1.39(t, 3 H, J = 7.1Hz), 2.69(s,3 H), 3.32(s, orated, and the residue was purified by PTLC [(2% MeOH3 H), 3.94 (4, 2 H,J = 7.1Hz), 4.19 (4, 2 H, J = 7.1Hz), 4.36 CH,Cl,)-(hexanes-EtOAc, 2:1),1:1]to afford 17j (19.6mg, 53%) (4, 2 H,J = 7.1Hz), 7.13-7.21(m, 6 H), 7.26-7.31(m, 4 H), 9.47 as a brown oil: 'H NMR (300 MHz, CDCl3) 6 1.41 (t, 6 H, J = (br s, 1 H); '3c NMR (75MHz, CDCl3) 6 11.69(q), 13.60(q), 14.19 7.0 Hz), 2.63(s, 6H),2.90(s, 3 H), 3.70(br s, 6 H), 4.39(q, 4 H, (q), 14.44(q), 33.18(q), 59.49(t),59.65(t),60.52(t),114.68(s), J = 7.0Hz), 5.03 (br s, 2 H), 5.09(br s, 2 H), 7.14 (br d, 4 H), 117.17(s), 120.57(s), 124.58(s), 126.11(d), 127.25(d), 127.87(d), 7.38(br s, 6 H), 8.89(br s, 2 H); 13C NMR (75MHz, CDC13) 6 128.09(s), 128.29(d), 129.54(s), 130.62(s), 130.82(d), 131.05(d),
J . Org. Chem. 1990,55, 918-924
918
11.61 (q), 14.41 (q), 32.42 (q), 51.69 (q), 60.55 (t), 65.85 (t),116.46 (s), 116.74 (s), 121.37 (s), 126.86 (s), 128.03 (d), 128.23 (d), 128.23 (s), 128.60 (d), 130.47 (s), 135.84 (s), 160.77 (s), 163.56 (s), 164.19 (5); IR (neat) 3268,2983,2953,1710,1455,1376,1304,1263,1214, 1147, 1061,736cm-'; MS (FAB) m / e (relative intensity) 768 [(M H)+,91,767 (M+,12), 91 (100);HRMS (FAB) m / e (M') calcd 767.2690, obsd 767.2670. trans- a n d cis-2',3'-Dihydro-2,2'-bipyrroles (20a,b). A solution of mesomeric betaine 10e (70.8 mg, 0.20 mmol) and dimethyl maleate (63.4 mg, 0.44 mmol) in benzene (4 mL) was heated at reflux for 6 h. The solvent was evaporated, and the residue was purified by PTLC [(hexanes-EtOAc, 3:l)-ether, 1:1] to afford 20a (69.5 mg, 70%) and 20b (8.3 mg,8%) as a pale yellow oils. In a similar experiment, a solution of 10e (70.8 mg, 0.20 mmol) and dimethyl fumarate (63.4 mg, 0.44 mmol) in benzene (4 mL) at reflux (3 h) afforded 20a (77.2 mg, 77%) and 20b (14.6 mg, 15%). 20a: 'H NMR (300 MHz, CDCl,) 6 1.36 (t, 3 H, J = 7.2 Hz), 1.41 (t, 3 H, J = 7.1 Hz), 2.54 (s, 3 H), 2.59 (s, 3 H), 3.47 (s, 3 H), 3.79 (s, 3 H), 3.85 (d, 1 H, J = 8.1 Hz), 4.18-4.28 (m, 1 H), 4.31-4.41 (m, 1 H), 4.38 (4, 2 H, J = 7.1 Hz), 5.47 (d, 1 H, J = 8.1 Hz), 7.44-7.48 (m, 5 H), 9.30 (br s, 1 H); 13C NMR (75 MHz, CDCl,) 6 11.75 (q), 14.36 (q), 14.36 (q), 35.74 (q), 50.40 (q), 52.18 (q), 54.85 (d), 59.93 (t), 60.58 (t),64.81 (d), 99.39 (s), 114.20 (s), 119.67 (s),128.18 (d), 128.93 (d), 129.62 (d), 130.77 (s), 130.99 (s), 139.30 (s), 161.33 (s), 163.67 (s), 164.43 (s),164.90 (s), 173.82 (9); IR (neat) 3250,2981,2949,1744,1699,1671,1615,1572,1437, 1305, 1247,1198,1076cm-'; MS (EI) m / e (relative intensity) 498 (M+,47), 466 (96), 438 (la),393 (loo), 347 (31), 315 (38), 118 (30); HRMS (EI) m / e (M+)calcd 498.2002, obsd 498.1992. 20a, 13C-
+
-,,
enriched: 13CNMR (75 MHz, CDC1,) 6 163.7 (s), 3Jc.5t = 3.3 = 0 Hz. 20b: 'H NMR (300 MHz, CD& 6 1.40 Hz, 3Jc.5,,~.2, (t,3 H, J = 7.2 Hz), 1.43 (t, 3 H, J = 7.2 Hz), 2.44 (s, 3 H), 2.58 (s, 3 H), 3.37 (s, 3 H), 3.48 (s, 3 H), 4.36 (q,4 H, J = 7.2 Hz), 4.45 (d, 1 H, J = 11.9 Hz), 5.52 (d, 1 H, J = 11.9 Hz), 7.45-7.47 (m, 5 H), 9.33 (br s, 1H); 13CNMR (75 MHz, CDCl,) 6 11.77 (q), 14.42 (q), 14.42 (q), 36.24 (q), 50.58 (q), 51.72 (q), 51.80 (d), 60.00 (t), 60.56 (t),64.97 (d), 101.81 (s), 115.29 (s), 119.73 (s), 128.23 (d), 128.79 (d), 129.46 (d), 130.49 (s), 131.47 (s), 136.15 (s), 161.28 (s), 164.66 (s),164.66 (s), 165.05 (s), 171.84 (5); IR (neat) 3256, 2983, 2947, 1742,1699,1620,1590,1436,1371,1245,1191,1072 cm-'; MS (EI) m / e (relative intensity) 498 (M+,34), 466 (58), 438 (lo), 393 (NO),347 (21),315 (25),118 (14);HRMS (EI) m / e (M+)calcd 498.2002, obsd 498.1999. 20b,13C-enriched: 13CNMR (75 MHz, CDClJ 6 165.1 (s), 3Jc.5,,~.3, = 3.7 Hz, 3Jc.5,,~.2, = 0 Hz.
Acknowledgment. Financial assistance from the National Science Foundation to Harvard University (Y. Kishi, CHE 86-105050) is gratefully acknowledged. We are grateful to Dr. J. Z. Gougoutas for valuable assistance during the course of this work and to the Squibb Institute Analytical Department for performing elemental analysis and HRMS measurements. Supplementary Material Available: 'H NMR spectra of 17i at 25 "C, 65 "C, and 130 "C; lH NMR and 13CNMR spectra of lOa,f-h, 12b, 17a-j, and 20a,b; and 13C NMR spectra of 13Cenriched samples of 10e, 17b,d and 20a,b (42 pages). Ordering information is given on any current masthead page.
Total Synthesis of (*)-7-Epi-20-desethylgelsedine Andrew S. Kende,* Michael J. Luzzio, and Jose S. Mendoza Department of Chemistry, University of Rochester, Rochester, New York 14627 Received July IO, 1989
The oxindole alkaloid gelsedine contains a unique molecular architecture. The synthetic approach to this pentacyclic molecule involved the efficient preparation of the all-cis trisubstituted pyrrolidine intermediate 14. The lactone system 18, an excellent precursor of the pentacyclic cage framework of gelsedine, was prepared in an efficient and highly convergent manner by reaction of pyrrolidine 16 and the readily available N-methoxyindole system 5. Subsequent steps led to the formation of the title compound.
Gelsedine (1) is an oxindole alkaloid that was isolated from Gelsemium sempervirens in 1953 by Schwarz a n d Marion.' Its structure was elucidated by Wenkert in 1962 through spectroscopic comparison with the related alkaloid Since that time synthetic studies toward gelsemicine (2)?s3
OMe
1, gelsedine ( X = H ) 2, gelsemicine ( X
=
OMe )
the total synthesis of gelsedine or gelsemicine have received scant attention in t h e literature, a n d t o date a successful synthesis of these alkaloids has not been r e p ~ r t e d . Very ~ recent activity toward the total synthesis of the Gelsemium alkaloids5 prompts us to describe our progress toward the total synthesis of gelsedine.6 Our retrosynthetic analysis to 1 is illustrated in Scheme I. We defined 20-desethylgelsedine (3) as a penultimate precursor of the target alkaloid, assuming that t h e C-20 ethyl (gelsedine numbering throughout the paper) could be introduced at the end of the sequence. T h e formation of t h e quaternary spirocyclic center at C-7 is the key structural problem in this pentacyclic skeleton. Recog(3) For reviews of literature related to Gelsemium alkaloids, see: (a) Saxton, J. E. In The Alkaloids; Manske, R. H. F., Eds.; Academic Press: New York, 1965; Vol. 8, pp 93-117. (b) Bindra, J. S., ref 3a, 1973, Vol. 14. DD .. 83-91. (4) Baldwin, S. W.; Doll, R. J. Tetrahedron Lett. 1979, 3275. (5) Choi, J. K.; Ha, D. C.; Hart, D. J.; Lee, C. S.; Ramesh, S.; Wu, S. J . Org. Chem. 1989, 54, 279. (6) Taken in part from Luzzio, M. J. Ph.D. Thesis, University of Rochester, 1987. 1
(1) Schwarz, H.; Marion, L. Can. J . Chem. 1953, 31, 958. (2) Wenkert, E.; Orr, J. C.; Garratt, S.; Hansen, J. H.; Wickberg, B.; Leicht, C. L. J . Org. Chem. 1962, 27, 4123.
0022-3263/90/1955-0918$02.50/0
0 1990 American Chemical Society
